Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases

Abstract

Stroke is one of the leading causes of death and disability worldwide. However, treatment options for ischemic stroke remain limited. Matrix-metalloproteinases (MMPs) contribute to brain damage during ischemic strokes by disrupting the blood-brain barrier (BBB) and causing brain edemas. Carnosine, an endogenous dipeptide, was found by us and others to be protective against ischemic brain injury. In this study, we investigated whether carnosine influences MMP activity. Brain MMP levels and activity were measured by gelatin zymography after permanent occlusion of the middle cerebral artery (pMCAO) in rats and in vitro enzyme assays. Carnosine significantly reduced infarct volume and edema. Gelatin zymography and in vitro enzyme assays showed that carnosine inhibited brain MMPs. We showed that carnosine inhibited both MMP-2 and MMP-9 activity by chelating zinc. Carnosine also reduced the ischemia-mediated degradation of the tight junction proteins that comprise the BBB. In summary, our findings show that carnosine inhibits MMP activity by chelating zinc, an essential MMP co-factor, resulting in the reduction of edema and brain injury. We believe that our findings shed new light on the neuroprotective mechanism of carnosine against ischemic brain damage.

Carnosine Alleviates Knee Osteoarthritis and Promotes Synoviocyte Protection via Activating the Nrf2/HO-1 Signaling Pathway: An In-Vivo and In-Vitro Study

“…Bae and colleagues investigated whether CA influences MMP activity in rats with cerebral ischemic injury. The gelatin zymology assay was used to measure MMP levels in the brain [ 115 ]. In another study, researchers investigated the effects of CA and gallic acid synesthetic peptides on MMP-2 and MMP-9 in human fibrosarcoma HT1080 cells [ 116 ].…”

Impact of MMP2 rs243849 and rs14070 genetic polymorphisms on the ischemic stroke susceptibility in Chinese Shaanxi population

“…MMP-2 was involved in the process of stroke injury in the early stage, and its activity and protein expression were obviously increased at this time ( 26 ). At the same time, Claudin-5 and occludin were degraded by MMP2 , the BBB was destroyed and the size of cerebral infarction increased ( 27 ). MMP2 can also promote endogenous repair, especially angiogenesis, cerebral blood flow reconstruction and repair of brain tissue damage in the recovery stage after stroke ( 25 ).…”

Matrix Metalloproteinases in Cardioembolic Stroke: From Background to Complications

“…The treatment was well tolerated and no toxic side effects were observed. The beneficial effect of carnosine is contributed to inhibition of tight-junction proteins damage, which results from the excessive activation of MMP-9 and MMP-2 in endothelial cells [ 162 ]. In animal studies, the effectiveness of doxycycline and minocycline, derivatives of tetracycline, in inhibiting MMP-2 and MMP-9 in a rat model of cerebral ischemia was confirmed [ 163 , 164 ].…”